TNF hampers intestinal tissue repair in colitis by restricting IL-22 bioavailability.

Autor: Ninnemann J; German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany., Winsauer C; German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany., Bondareva M; German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany.; Belozersky Institute of Physico-Chemical Biology and Faculty of Bioengineering and Bioinformatics, M.V. Lomonosov Moscow State University, Moscow, Russia., Kühl AA; iPATH.Berlin, Core Unit of Charité-Universitätsmedizin Berlin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany., Lozza L; Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany., Durek P; German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany., Lissner D; Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany., Siegmund B; Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany., Kaufmann SHE; Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany., Mashreghi MF; German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany., Nedospasov SA; Belozersky Institute of Physico-Chemical Biology and Faculty of Bioengineering and Bioinformatics, M.V. Lomonosov Moscow State University, Moscow, Russia.; Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.; Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, Berlin, Germany., Kruglov AA; German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany. kruglov@drfz.de.; Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia. kruglov@drfz.de.; Belozersky Institute of Physico-Chemical Biology and Biological Faculty, M.V. Lomonosov Moscow State University, Moscow, Russia. kruglov@drfz.de.
Jazyk: angličtina
Zdroj: Mucosal immunology [Mucosal Immunol] 2022 Apr; Vol. 15 (4), pp. 698-716. Date of Electronic Publication: 2022 Apr 05.
DOI: 10.1038/s41385-022-00506-x
Abstrakt: Successful treatment of chronic inflammatory diseases integrates both the cessation of inflammation and the induction of adequate tissue repair processes. Strikingly, targeting a single proinflammatory cytokine, tumor necrosis factor (TNF), induces both processes in a relevant cohort of inflammatory bowel disease (IBD) patients. However, the molecular mechanisms underlying intestinal repair following TNF blockade during IBD remain elusive. Using a novel humanized model of experimental colitis, we demonstrate that TNF interfered with the tissue repair program via induction of a soluble natural antagonist of IL-22 (IL-22Ra2; IL-22BP) in the colon and abrogated IL-22/STAT3-mediated mucosal repair during colitis. Furthermore, membrane-bound TNF expressed by T cells perpetuated colonic inflammation, while soluble TNF produced by epithelial cells (IECs) induced IL-22BP expression in colonic dendritic cells (DCs) and dampened IL-22-driven restitution of colonic epithelial functions. Finally, TNF induced IL-22BP expression in human monocyte-derived DCs and levels of IL22-BP correlated with TNF in sera of IBD patients. Thus, our data can explain how anti-TNF therapy induces mucosal healing by increasing IL-22 availability and implicates new therapeutic opportunities for IBD.
(© 2022. The Author(s).)
Databáze: MEDLINE
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